The hallmark of fibrosis is the excessive deposit of extracellular matrix components caused by an increased synthesis and decreased degradation of matrix proteins, predominantly collagen type I and III. This process of fibrosis can occur in all kinds of organs such as the kidney (glomerulosclerosis or interstitial fibrosis), the skin (scar formation), the lung and also in the liver, where the end-stage of liver fibrosis is referred to as cirrhosis. The process also shares many characteristics with the formation of atherosclerotic plaques in arteries. Liver fibrosis leads to a deterioration of liver function, and eventually in complete liver failure, which is lethal if untreated. The process can be elicited by viruses (Hepatitis A, B and C), alcohol consumption, genetic disorders, or by chronic exposure to hepatotoxic agents. The incidence of this disease is very variable depending on the country. In the period 1985-1989, the incidence of liver cirrhosis in The Netherlands was 3.90 per 100,000 habitants per year, whereas this incidence in, for instance, France and Germany was 11.9 respectively 12.4. To date, no effective pharmacotherapeutic intervention is available for this disease. In the past decades liver transplantation has become a serious option for many patients but the costs, the availability of donor livers and the traumatic event of the transplantation itself hamper the application of such an operation in general practice. Pharmacological intervention would be a better option.
Hepatic stellate cells (HSC), also called Ito cells or fat storing cells strongly proliferate during the progression of the disease and they subsequently transform into myofibroblasts (MF). These cells are the major producers of collagens, glycoproteins, and proteoglycans in a diseased liver. Moreover, HSC and MF produce an array of mediators which activate other hepatic and inflammatory cells thus enhancing the fibrotic process. Therefore, HSC are an important target for anti-fibrotic therapy. However, in vivo studies indicate that anti-fibrotic drugs are not efficiently taken up by HSC and as a consequence, most drugs which showed potent anti-fibrotic activity in vitro, failed to exert any effect in vivo. At high doses such drugs often induce many side effects caused by extrahepatic distribution of the drug. Cell specific delivery is an option to solve these problems. This can be accomplished by coupling drugs to carrier molecules, which are selectively taken up by the target cells. Liposomes are well known drug carriers but modified proteins can also be applied. Cell specific delivery of therapeutic and diagnostic agents to hepatocytes, endothelial and Kupffer cells has already been achieved by modification of the sugar moieties of proteins or polymers. Coupling of galactose to, for instance, human serum albumin (HSA) leads to a specific accumulation of this neoglycoprotein in hepatocytes whereas addition of mannose to albumin causes uptake into Kupffer or endothelial cells. Increasing the net negative charge (for instance by succinylation of amine groups) results in uptake of the protein into endothelial cells via scavenger receptors. For a comprehensive review on carrier devices for cell specific delivery of drugs see D. K. F. Meijer and G. Molema, Sem. in Liver Dis. 15: 202-256, 1995. The benefits of such carrier devices for the development of novel pharmacotherapeutic interventions for various diseases has been well recognized. However, a specific carrier for drugs to HSC, the most important cell in the pathogenesis of liver fibrosis, has not been found yet.